Metal ligand complexes are routinely used for medicinal applications. For example, gadolinium complexes (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) are used to enhance the quality of magnetic resonance imaging. Gd-DTPA has been utilized in studying abnormalities of the gastrointestinal tract, liver, and kidneys as well as visualizing heart infarcts. [See I. K. Adzaml., J. Nucl. Med. 32, 139 (1989).] When radioactive metal ions are used, diagnostic imaging or therapy can be the end objective. Thus .sup.99m Tc, a pure gamma emitter, in the form of a metal ligand complex is routinely used as a diagnostic agent. In some cases, such as the use of .sup.99m Tc-DTPA, injection of the complex into the bloodstream does not result in the radionuclide localizing in any tissue. Instead, the radionuclide is eliminated from the body by the kidneys into the urine. In other cases, the radionuclide does localize in desired specific organs or tissues. Thus specific .sup.99m Tc-phosphonic acid complexes localize in bone [Radiology 149, 823-828 (1983)] and one of the uses of .sup.99m Tc-phosphonic acid complexes is the detection of calcific tumors.
More recently, similar chemistry has been used to deliver particle emitting radionuclides to calcific tumors. The aim of these agents is to deliver a therapeutic radiation dose to the site of the tumor. This type of agent takes advantage of fast bone turnover for its localization. Thus Deutsch et al. [Radiology 166, 501-507 (1988)] have proposed a rhenium-diphosphonate for the treatment of bone cancers and Simon et al. (U.S. Pat. No. 4,898,724) have taught the use of rare earth radionuclides with aminophosphonic acids towards the same objective.
The specific delivery of metals to soft tissue (i.e. non-calcific) tumors has also been an objective for scientists. Anghilery in Nuklearmedizin 23, 9-14 (1984) describes the difficulty in achieving this objective when he states that "there are no fundamental qualitative differences in the structural, biochemical and functional characteristics of a tumor compared to the normal cell." With the advent of monoclonal antibodies, a plethora of activity has emerged using these proteins to deliver radionuclides to soft tissue tumors [e.g. A. R. Fritzberg et al., Pharm. Res. 5(6), 325 (1988)]. Bifunctional chelating agents were developed to bind the metal ions to the monoclonal antibody through a chelating agent (the metal-ligand-antibody moiety is termed a "conjugate") and many such conjugates have emerged. Some conjugates use gamma emitters such as .sup.99m Tc or .sup.111 In for imaging (see for example U.S. Pat. Nos. 4,454,106, 3,994,966, 4,662,420 and 4,479,930); and others propose a conjugate with particle emmiters such as .sup.67 Cu [see for example J. C. Roberts et al., Appl. Rad. Isotopes 40(9), 775 (1989)] or .sup.90 Y [see for example J. Nucl. Med. 26(5), 503 (1985)] for therapy. It was believed that the use of the conjugates provided the answer to the site specific delivery of a radioactive metal ion to soft tissue tumors. However, in the practice of the use of these conjugates a series of problems has been observed. For example, problems have been noted involving the fragile nature of the antibody, the slow clearance of the radioactivity from the blood stream, the uptake of radioactivity in non-target tissues such as liver and kidney, and the potential of an immune response of the patient to the injected protein.
Another approach to delivering metals to soft tissue tumors is by means of a metal ligand complex. Although this approach has not been pursued in the recent literature, it has received extensive attention in earlier literature. The recognition by Andrews et al. in Radiology 61, 570-599 (1953) that Ga.sup.+3 had a tendency to localize in soft tissue tumors led to the development of .sup.67 Ga-citrate as a tumor imaging agent [R. L. Hayes, Int. J. Nucl. Med. Biol. 10(4), 257-251 (1983)]. Although .sup.67 Ga-citrate is presently used for detecting abscesses more than for tumor diagnosis, many clinicians prefer to use it over the monoclonal antibody conjugates for diagnosis. Even though .sup.67 Ga-citrate is widely used, it has various disadvantages. For example, the rate of blood clearance is slow so that images are taken as much as 48 hours post injection with .sup.67 Ga-citrate [see Int. J. Appl. Nucl. Med. Biol. 8, 249-255 (1984)]. In addition, high uptake of the .sup.67 Ga-citrate in non-target tissues make images difficult to interpret [see Curr. Concepts in Diagn. Nucl. Med. 1(4), 3-12 (1984)].
In attempts to obtain more useful complexes for delivery of metal ions to soft tissue tumors, certain aminocarboxylic acid complexes have been used. For example, Karube et al. in Chem. Pharm. Bull. 30(7), 2529-2533 (1982) found that .sup.99m Tc-ethylenediaminediacetic acid (EDDA) and .sup.57 Co-EDDA could be used to image tumors in experimental animals bearing Ehrlich tumors. However, .sup.99m Tc complexes with other ligands were less effective. Some of the ligands tested with .sup.99m Tc were iminodiacetic acid (IDA), methyliminodiacetic acid (MIDA), nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA), and hydroxyethylethylenediaminetriacetic acid (HEDTA). Woolfenden et al. in Int. J. Nucl. Med. 10(4), 251-256 (1983) found that .sup.153 Sm-citrate and .sup.153 Sm-chloride had a high liver uptake and suggested the use of higher stability chelates, such as .sup.153 Sm-EDTA, could improve the tumor to liver ratio. More recently, J. Harvey Turner in Eur. J. Nucl. Med. 13, 432-438 (1987) studied .sup.153 Sm chelates including HEDTA. The .sup.153 Sm-HEDTA chelates used a 20 to 1 HEDTA to Sm molar ratio and found tumor uptake to be significantly less than that of .sup.67 Ga-citrate. An unacceptably large liver uptake was noted when using .sup.153 Sm-HEDTA at these ratios. He concluded that "it is unlikely that effective therapy doses of Sm-153 can be delivered to melanoma tumors by these and similar chelates." He suggested the use of monoclonal antibodies with .sup.153 Sm. Another attempt to have complexes deliver metal ions to soft tissue tumors was made by Tse et al. in J. Nucl. Med. 30, 202-208 (1989) where they studied .sup.153 Sm-EDTA at a 10 to 1 ligand to metal molar ratio. These researchers proved that the complex was stable and compared the use of high specific activity .sup.153 Sm (1.7 Ci/mG) to low specific activity .sup.153 Sm (1.1 mCi/mG) in mice bearing Lewis lung carcinoma. They propose using the complex as an imaging agent using the high specific activity .sup.153 Sm. However, as J. Harvey Turner had reported for .sup.153 Sm-HEDTA, these researchers also found significant uptake in the liver as shown by their biodistribution and images.
Therefore, there is still a need for an adequate system to deliver radionuclides selectively to soft tissue tumors. Surprisingly, it has now been found that various metal-ligand complexes wherein the ligand is an aminocarboxylate containing a phenolic moiety, particularly the metal-Bis-IDA complex, preferably with a high ligand to metal ratio, such as at least 50:1, give good soft tissue tumor localization with no significant liver uptake and can be used as diagnostic or therapeutic agents.